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RU2017126601A - Способы и композиции для лечения злокачественных опухолей, ассоциированных с мутацией kras - Google Patents

Способы и композиции для лечения злокачественных опухолей, ассоциированных с мутацией kras Download PDF

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RU2017126601A
RU2017126601A RU2017126601A RU2017126601A RU2017126601A RU 2017126601 A RU2017126601 A RU 2017126601A RU 2017126601 A RU2017126601 A RU 2017126601A RU 2017126601 A RU2017126601 A RU 2017126601A RU 2017126601 A RU2017126601 A RU 2017126601A
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introduction
gst
rnai molecules
tumor
mammal
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RU2017126601A
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Венбин ИН
Кендзироу МИНОМИ
Бхарат МАДЖЕТИ
Ли ВАНГ
Цзихуа ЛЮ
Роджер Адами
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Нитто Денко Корпорейшн
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Claims (33)

1. Фармацевтическая композиция для лечения или терапии опухоли, ассоциированной с мутацией в гене KRAS или со сверхэкспрессией гена KRAS дикого типа, причем композиция содержит молекулы РНКи и фармацевтически приемлемые вспомогательные вещества, где молекулы РНКи содержат нуклеотидную последовательность, соответствующую последовательности-мишени GST-π.
2. Фармацевтическая композиция по п.1, где молекулы РНКи содержат дуплексную область, содержащую нуклеотидную последовательность, соответствующую последовательности-мишени SEQ ID NO: 287.
3. Фармацевтическая композиция по п.1, где молекулы РНКи содержат антисмысловую цепь, содержащую нуклеотидную последовательность, соответствующую SEQ ID NO: 184, и смысловую цепь, содержащую нуклеотидную последовательность, соответствующую SEQ ID NO: 158.
4. Фармацевтическая композиция по п.1, где молекулы РНКи представляют собой киРНК или кшРНК.
5. Фармацевтическая композиция по п.1, где фармацевтически приемлемые вспомогательные вещества включают одно или более липидных соединений.
6. Фармацевтическая композиция по п.1, где фармацевтически приемлемые вспомогательные вещества включают липидные наночастицы.
7. Фармацевтическая композиция по п.1, где фармацевтически приемлемые вспомогательные вещества включают липидные наночастицы, которые инкапсулируют молекулы РНКи.
8. Способ предотвращения, лечения или ослабления одного или более симптомов злокачественной опухоли, ассоциированной с мутацией KRAS у млекопитающего, нуждающегося в этом, причем способ включает:
идентификацию опухолевой клетки у млекопитающего, причем опухолевая клетка содержит, по меньшей мере, одно из следующего: (i) мутацию гена KRAS и (ii) уровень аберрантной экспрессии белка KRAS; и
введение млекопитающему терапевтически эффективного количества композиции, содержащей одну или более молекул РНКи, которые активны в снижении экспрессии GST-π.
9. Способ по п.8, где млекопитающее представляет собой человека, а GST-π представляет собой человеческий GST-π.
10. Способ по п.8, где молекула РНКи представляет собой киРНК или кшРНК.
11. Способ по п.8, где молекулы РНКи содержат дуплексную область, содержащую нуклеотидную последовательность, соответствующую последовательности-мишени SEQ ID NO: 287.
12. Способ по п.8, где молекулы РНКи содержат антисмысловую цепь, содержащую нуклеотидную последовательность, соответствующую SEQ ID NO: 184, и смысловую цепь, содержащую нуклеотидную последовательность, соответствующую SEQ ID NO: 158.
13. Способ по п.8, где молекула РНКи уменьшает экспрессию GST-π у млекопитающего.
14. Способ по п.8, где введение уменьшает экспрессию GST-π у млекопитающего, по меньшей мере, на 5% в течение, по меньшей мере, 5 дней.
15. Способ по п.8, где введение уменьшает объем злокачественной опухоли у млекопитающего, по меньшей мере, на 5% или, по меньшей мере, на 10% или, по меньшей мере, на 20% или, по меньшей мере, на 30% или, по меньшей мере, на 40% или, по меньшей мере, на 50%.
16. Способ по п.8, где способ уменьшает один или более симптомов злокачественной опухоли или задерживает или прекращает прогрессирование злокачественной опухоли.
17. Способ по п.8, где введение уменьшает рост злокачественных опухолевых клеток у объекта.
18. Способ по п.8, где введение уменьшает рост, по меньшей мере, на 2% или, по меньшей мере, на 5% или, по меньшей мере, на 10% или, по меньшей мере, на 15% или, по меньшей мере, на 20% злокачественных опухолевых клеток у объекта.
19. Способ по п.8, где опухолевые клетки содержат повышенный уровень экспрессии белка KRAS дикого типа по сравнению с таковым в нормальной клетке.
20. Способ по п.8, где опухолевая клетка сверхэкспрессирует РНК или белок GST-π дикого типа.
21. Способ по п.8, где опухолевая клетка содержит мутации в белке KRAS в одном или более из остатков 12, 13 и 61.
22. Способ по п.8, где опухолевая клетка содержит мутации в белке KRAS, и опухоль представляет собой злокачественное новообразование, выбранное из рака легких, рака толстой кишки и рака поджелудочной железы.
23. Способ по п.8, где опухолевая клетка содержит мутации в белке KRAS, и опухоль представляет собой саркому, выбранную из группы, состоящей из аденокарциномы легкого, муцинозной аденомы, протоковой карциномы поджелудочной железы и колоректальной карциномы.
24. Способ по п.8, где злокачественная опухоль представляет собой саркому, выбранную из группы, состоящей из аденокарциномы легкого, муцинозной аденомы, протоковой карциномы поджелудочной железы, колоректальной карциномы, рака молочной железы и фибросаркомы.
25. Способ по п.8, где злокачественная опухоль локализована в анатомической области, выбранной из группы, состоящей из легкого, толстой кишки, поджелудочной железы, желчного пузыря, печени, молочной железы и любой их комбинации.
26. Способ по п.8, где введение осуществляют от 1 до 12 раз в день.
27. Способ по п.8, где введение осуществляют в течение 1, 2, 3, 4, 5, 6 или 7 дней.
28. Способ по п.8, где введение осуществляют в течение 1, 2, 3, 4, 5, 6, 8, 10 или 12 недель.
29. Способ по п.8, где введение представляет собой дозу от 0,01 до 2 мг/кг молекул РНКи, по меньшей мере, один раз в день в течение периода до двенадцати недель.
30. Способ по п.8, где введение обеспечивает среднее AUC (0-конец) от 1 до 1000 мкг*мин/мл и среднее значение Cmax от 0,1 до 50 мкг/мл для молекулы GST-π РНКи.
31. Способ по п.8, где введение представляет собой внутривенную инъекцию, внутрикожную инъекцию, подкожную инъекцию, внутримышечную инъекцию, внутрибрюшинную инъекцию, пероральное введение, местное введение, инфузию или ингаляцию.
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